Antibody Neutralization of Therapeutic Viruses

描述(申请人提供)：多发性骨髓瘤是一种无法治愈的、播散性的终末分化浆细胞恶性肿瘤，2006年将导致11,000多名美国人死亡。减毒麻疹病毒对表达丰富的CD46(病毒受体)的人骨髓瘤浆细胞具有选择性的破坏性，在小鼠骨髓瘤异种移植模型中具有治疗作用。因此，我们正在对晚期难治性多发性骨髓瘤患者静脉注射重组麻疹病毒进行测试。中和抗麻疹抗体预计会限制系统注射的麻疹病毒的治疗效果，特别是在抗体效价较高的70%的骨髓瘤患者中。这项提议的目标是制定最佳策略，通过抑制抗麻疹抗体的产生，或通过在体外感染的自体单核细胞或树突状细胞内传递病毒，来对抗血液中的麻疹病毒。这些研究的结果将被用来指导未来对骨髓瘤患者进行麻疹病毒治疗的临床试验的设计。具体目标如下：目的1.制定一种临床可行的策略，使用环磷酰胺与麻疹加强免疫相结合，以降低中和抗麻疹抗体的血浆浓度。目的2.评价麻疹感染的单核细胞或单核细胞来源的树突状细胞(未成熟或成熟)作为抗体抗性病毒载体的性能。目的3.确定抑制CCR7趋化因子受体的表达是否有利于影响麻疹感染的树突状细胞在CD46转基因SCID小鼠体内的生物分布。 公共卫生相关性：抗体是病毒作为抗癌剂成功部署的最重要障碍。这笔赠款旨在为这一问题开发临床可行的解决方案。

DESCRIPTION (provided by applicant): Multiple myeloma is an incurable, disseminated malignancy of terminally differentiated plasma cells that will be responsible for the deaths of more than 11,000 Americans in 2006. Attenuated measles viruses are selectively destructive to human myeloma plasma cells which express abundant CD46 (the viral receptor) and are therapeutically potent in murine myeloma xenograft models. We are therefore testing a recombinant measles virus by intravenous administration in patients with advanced, treatment-refractory multiple myeloma. Neutralizing antimeasles antibodies are expected to limit the therapeutic efficacy of the systemically administered measles viruses, particularly in those 70% of myeloma patients with higher antibody titers. The goal of this proposal is to develop optimal strategies to combat measles virus neutralization in the bloodstream by suppressing the production of antimeasles antibodies, or by delivering the virus inside autologous monocytes or dendritic cells, infected outside the body. The findings of these studies will be used to guide the design of future clinical trials of measles virotherapy in myeloma patients. Specific aims are as follows: Aim 1. Develop a clinically viable strategy using cyclophosphamide in combination with measles booster vaccination to reduce the plasma concentration of neutralizing anti-measles antibodies. Aim 2. Evaluate the performance of measles-infected monocytes, or monocyte-derived dendritic cells (immature or mature) as antibody-resistant virus delivery vehicles. Aim 3. Determine whether suppression of CCR7 chemokine receptor expression can favorably impact the biodistribution of measles-infected dendritic cells in CD46 transgenic SCID mice. Public Health Relevance: Antibodies are the most important barrier to the successful deployment of viruses as anticancer agents. This grant seeks to develop clinical viable solutions to this problem.